Tertiary arylamines and process of making same



Patented Apr. 25,1950

' Karl Miescher and Willi Klarer, Bichen, Switzerland, assignors to Ciba Pharmaceutical Products Inc., Summit, N. .1.

N6 Drawing. Application March 10, 1945, Serial N0. 582,190. In Switzerland March- 31,- 1944 According to the present invention tertiary arylamines are obtained by causing mono-salts of compounds of the formula wherein R stands for an alkylene chain, X stands for a secondary arylamine group the nitrogen atom of which is connected with R, and Y stands for a stronger basic group, to react with reactive esters of alcohols.

As mono-salts of compounds of the foregoing formula there are particularly used mono-salts of strong acids, such as mono-salts of hydrohalogen acids, of sulfuric acid, of nitric acid, and of alkyl-, aralkylor arylsulfom'c acids. In the indicated starting materials the arylamino group X may represent for example an unsubstituted or substituted aniline radical. As substituentsthere' are named alkyl, alkenyl, nitro, free, esterified, or etherified hydroxy groups. The alkylene chain may be straight, branched or be part of a ring. Compounds having an ethylene, propylene,.dec amethylene, 2:2-dimethyl-pr0pylene or cyclohexylene radical are thus suitable. The group Y represents a primary, secondary or tertiary amino group" such as e. g. a monoand djialkylami'r'io, piperi'din'o, morpholino, guanidino', am'idino; iniidazolono or tetrahydro-pyrimidino group.

Among reactive esters of alcohols are included esters of hydrohalogen acids, alkyl or aryl sulfonic acids. The alcohol radical may belong to the aliphatic; araliphatie, alicyclic or heterocyclic series; as examples there are named the methyl, ethyl, octyl, allyl, benzyl or cyclohexyl radical.

The reaction itself is carried out in the presence or absence of diluents, such as alcohol or dioxane, and it is also possible to work in the presence of catalysts.

The present process has proved to be particularly advantageous. Experiments which applicants have carri d out have shown that N-(fl-dimethylaminoethyD- or ,N-w-dimethyl-aminopropyl)-N-benzylani1ine from N-benzylaniline and ,B-dimethylamino-ethylor w-dimethylaminopropyl-chloride, respectively, can be obtained only in poor yield. Moreover, N-benzyl-Z-methylaniline could not be converted into N-(fi-diethylamino-ethyl)-N-benzyl-Z-methylaniline with ,8- diethylamino-ethyl-chloride. Further, it has been ascertained that in thereaction of N-(fidimethylamino-ethyl)-aniline With benzylchloride the tertiary nitrogen atom forms a quaternary compound. Besides, it is surprising that in the reaction according to the present process free NH- or Niizagroups within the radical Y are not 9 Claims. (01. 260-4096) SAME attacked and quaternary compounds are not formed.

The new compounds possess therapeutic activities and can be used as therapeutic substances or as intermediate products for the manufacture thereof.

The following examples illustrate the invention, but are not to be" regarded as limiting it in any way,- the parts beingby weight.

Example 1 20 parts of N (fi-dimethyl'amino-ethyl) -anilinemonohydrochloride in 50 parts of absolute alcohol are" heated to boiling for some hours on the waterbatli with 7 parts of allylbromid'e. The alcohol is distilled off and the residue taken up in water. After addition of alkali the whole is extracted with ether and the residue of the ethereal extract subjected to distillation, the N-aJllyl-N-(fi-dir'nthylamino-ethyl) -aniline which has been formed passing over at 138-141 C. under 11mm. pressure. A mono-hydrochloride of melting point I6'O"-161 C'. is formed.

Instead of the hydrochloride of N-(B-dimethylamino-ethyl) -aniline also the salt of another strong acid, for example the salt of hydrobromic acid,- sulfuric acid, nitric acid or of an alkylor an arylsulfonic acid may be caused to react.

Instead of all ylbromide there can also be used all'ylchloride;

The same compound also obtained when starting from the free N-(fi-dimethylaminoeth -amunearid a'- quantity of alcoholic hydrochloricacid corresponding to the mono-hydrochloride;

Example 2' 242 parts of N-('y-diethylamino-propyl)-anifine-mononyurccnior de (of melting point 122- 123 CL; obtained from aniline and 'yediethyl amino-propylchloride-hydrochloride) are dissolve in 1'00 parts of absolute alcohol and heated to boiling for several hours on the Water-bath with 7 parts of benz'ylchloride. The product is worked up as described in Example 1*; The N- benzyl-N- (y-diethylamino+propyl) -aniline is distilled at 218219 C. under 10 mm. pressure; its mono-hydrochloride melts at 131-182 C'.

The same compound obtained when using benzyl bromide or benzyl-para-toluene-sulfonic acid' ester instead of benzylchloride.

El'tam'ple 3' A-s'olut'ion of 34 4 parts of N ('y-dimethylamino propyn- 2' anisidiriemioli'e hydrochloride (of melting point 152-l53 0.; prepared by reaction of 'y-dimethylamino-propyl-chloride hydrochloride with 2-anisidine) in 100 parts of absolute alcohol is kept boiling for a long time with '7 parts of benzylchloride. After distilling ofi the alcohol in a vacuum, the N-benzyl-N-(y-dimethylamino-propyl) -2-anisidine is isolated from the residue, as described in Example 1. The new base boils at 208-210 C. under 11 mm. pressure; its mono-hydrochloride melts at 151-152 C.

Instead of 24.4 parts, there can also be used 12.2 parts of N-('y-dimethylamino-propyl) -2- anisidine in the above reaction, the acid which has been formed being neutralized in the course of the reaction by addition of, e. g. sodium ethylate.

Example 4 If 18.6 parts of N-(p-methylaminoethyl)-aniline-mono-hydrochloride are caused to react with '7 parts of benzylchloride as described in the foregoing examples, there is obtained N-benzyl-N- (,B-methylamino-ethyl)-aniline of boiling point 210-212 C. under 13 mm. pressure, the monohydrochloride of which melts at I'M-175 C.

By methylating the base with dimethylsulfate there is obtained the N-benzyl-N-(p-dimethylamino-ethyD-aniline (mono-hydrochloride of melting point ZOO-202 C.). This base can also be obtained by causing N-(fl-dimethylaminoethyl) -aniline-mono-hydrochloride to react with benzyl chloride.

Example 5 If 17.2 parts of N -(,B-amino-ethyl) -anilinemono-hydrochloride are caused to react with '7 parts of benzylchloride, as indicated in Example 1, there is obtained N-benzyl-N-(,B-amino-ethyl) aniline of boiling point 206-208 C. under 14 mm. pressure (mono-hydrochloride melts at 193-194 C.)

Determination of the nitrogen according to Van Slyke has shown that in this kind of reaction the primary amino group of N-(fl-aminoethyD-aniline remains unattached.

Example 6' A solution of 21 parts of Z-(phenylaminomethyl) -imidazo1ine-mono-hydrochloride and 8 parts of benzylchloride in 100 parts of alcohol is boiled for some hours in a reflux condenser. The solvent is then distilled 01f, the residue mixed with water and neutralized with sodium bicarbonate. The 2-(N-phenyl-N-benzyl-aminomethyl) -imidazoline hydrochloride which has precipitated after a short time is suction-filtered. After recrystallization from little water it melts at 227- 229 C.

In this reaction the alcohol can be also replaced by another solvent, e. g. butyl alcohol, dioxane or benzylchloride itself.

The following compounds, for example, can also be prepared analogously to the processes described in the foregoing examples:

N- (,B-diethylamino-ethyl) N ethyl aniline of boiling point 149-150 C. under 11 mm. pressure;

N- (p-diethylamino-ethyl) -N benzyl aniline of boiling point 209-210 C. under 11 mm. pressure;

N- (,S-dimethylamino-ethyl) -N-benzyl-2- methylaniline of boiling point 181l84 C. under 11 mm. pressure;

N-(p-dimethylamino-ethyl) -N-benzyl 2 methoxy-aniline of boiling point ZOO-206 C. under 11 mm. pressure;

N-(p-dimethylamino-ethyl) -N-benzyl 4 methoxy-aniline of boiling point 219-22l C. under 12 mm. pressure;

N- (,c-dimethylamino-ethyl) -N-benzyl-2- ethoxy- 5-methyl-aniline of boiling point 141-143 C. under 0.1 mm. pressure;

N- (p-dimethylamino-ethyl) -N-benzyl-2- ethoxyaniline of boiling point 200-203 C. under 10 mm. pressure;

N- (p-dimethylamino-ethyl) -N-phenylethylaniline of boiling point 210-211 C. under 12 mm. pressure;

N- (,B-dimethylamino-ethyl) -N- (4- methoxybenzyl) -aniline of boiling point 225-227 C. under 12 mm. pressure;

N- (p-dimethylamino-ethyl) -N- (3' methoxybenzyl) -aniline of boiling point 217-2l8 C. under 12 mm. pressure;

N-(p-piperidino-ethyl) -N-benzyl-aniline of boiling point 201-205" C. under 0.1 mm. pressure; N-(p-piperidino-ethyl) -N (3 methoxybenzyl) aniline of boiling point 215-2l8 C. under 0.8

mm. pressure;

2-[N-(2-rnethoxyphenol) N benzyl aminomethyll imidazoline hydrochloride of melting point 168-169 C.;

2-[N (4 methoxyphenyl) N benzyl amino methylJ-imidazoline hydrochloride of melting point 206-208 C.;

2- [N- 2'-ethoxyphenyl) N benzyl-aminomethyl] -imidazcline hydrochloride of melting point 187-188 C.;

2-[N- (4-ethoxyphenyl) N benzyl-aminomethyll -imidazoline hydrochloride of melting point 216-218" C.;

Z-[N-naphthyl- (1) N benzyl aminomethyllimidazoline hydrochloride of melting point 207- 209 C.;

Z-EN-phenyl-N-benzyl aminopropyl] irnidazcline hydrochloride of melting point 193195 C.;

2- [fl- (N-phenyl-N-benzyl-amino) -ethyl-a1nino] imidazoline hydrochloride of melting point 116 C.

The parent materials used for the production of the above compounds, as far as they are not known, may be prepared according to known methods.

What we claim is:

1. Process for the manufacture of a tertiary arylamine which comprises causing a mono-salt of a strong acid of a compound of the formula wherein R stands for an alkylene chain, X for an aryl radical and Y represents a member of the group consisting of the amino group, monoand dialkylainino and amidino groups, to react with an ester of an acid of the group consisting of hydrohalogen acids and sulfonic acids with an alcohol of the group consisting of aliphatic and aralipha tic alcohols.

2. Process for the manufacture of a tertiary arylamine which comprises causing a mono-salt of a strong acid of a compound of the formula wherein R. stands for an alkylene chain, X for a phenyl radical, and Y represents an imidazoline group, to react with an ester of a hydrohalogen acid with an alcohol of the group consisting of aliphatic and araliphatic alcohols.

3. Process for the manufacture of a tertiary arylamine, comprising causing an N-(p-dialkylamino-alkyl) aniline mono hydrogen halide salt to react with an araliphatic halide.

4. Process for the manufacture of a tertiary arylamine, comprising causing N-(p-dimethylamino-ethyl)-aniline-mono-hydroohloride to react with benzyl chloride.

5. Process for the manufacture of a tertiary arylamine, comprising causing 2- [,B- (phenylam ino) ethylamino] imidazoline mono hydrochloride to react with benzyl chloride.

6. Process for the manufacture of a tertiary arylamine, comprising causing a 2-(phenyl-amino-alkyl) -imidazoline mono hydrogen halide salt to react with an araliphatic halide.

7. Process for the manufacture of a tertiary arylamine, comprising causing Z-(phenylaminomethyl) -imidazoline-mono-hydroch1oride to react with benzyl chloride.

8. Z-[p-(N-phenyl N benzyl amino) -ethylamino] -imidazoline.

9. In the process of making N-benzyl-N- phenyl-N,N'-dimethyl-ethylenediamine the step comprising heating in an organic solvent a mixture of the monohydrochloride of N-phenyl- REFERENCES CITED The following references are of record in the file of this patent:

UNITED STATES PATENTS France Mar. 27, 1940 Certificate of Correction Patent No. 2,505,133 April 25, 1950 KARL MIESOHER ET AL It is hereby certified that error appears in the printed specification of the above 7 numbered patent requiring correction as follows:

Column 3, line 13, for the Word unattached read unattaclced;

and that the said Letters Patent should be read with this correction therein that the same may conform to the record of the case in the Patent Oflice.

Signed and sealed this 22nd day of August, A. D. 1950.

THOMAS F. MURPHY,

Assistant Gommz'ssioner of Patents. 

1. PROCESS FOR THE MANUFACTURE OF A TERTIARY ARYLAMINE WHICH COMPRISES CAUSING A MONO-SALT OF A STRONG ACID OF A COMPOUND OF THE FORMULA 